Interleukin-6 (IL-6) is a multifunctional regulator of immune response and hematopoiesis. Recently, it has been reported that expression of IL-6 is correlated with prognosis in various cancer patients. In this study, we investigated whether the proliferation and invasion potential of head and neck squamous cell carcinomas (HNSCCs) were influenced by IL-6. All HNSCC cell lines, HEp-2, HSC-2, HSC-4, and SAS, were tested by reverse transcription-polymerase chain reaction (RT-PCR) and expressed the IL-6 receptor (IL-6R), and glycoprotein 130, which is responsible for signal transduction. HEp-2, HSC-2, and HSC-4 also produced IL-6. IL-6 inhibited the proliferation of HSC-2 and SAS, but the invasion potential of all the cell lines increased. Moreover, IL-6 down-regulated soluble IL-6R expression. Anti-IL-6R antibody abrogated the inhibited proliferation and increased invasion induced by IL-6. IL-6 stimulation also induced the extracellular regulated protein kinase 1/2 activation and increased vascular endothelial growth factor release. These results suggest that IL-6 can directly influence cell proliferation and the invasion potential as the first step of tumor metastasis.